Fused tricyclic pyrrolizinones that exhibit pseudo-irreversible blockade of the NK1 receptor

Previously, we had disclosed a novel class of hNK1 antagonists based on the 5,5-fused pyrrolidine core. These compounds displayed subnanomolar hNK1 affinity along with good efficacy in a gerbil foot-tapping (GFT) model, but unfortunately they had low to moderate functional antagonist (IP-1) activity. To elaborate on the SAR of this class of hNK1 compounds and to improve functional activity, we have designed and synthesized a new class of hNK1 antagonist with a third fused ring. Compared to the 5,5-fused pyrrolidine class, these 5,5,5-fused tricyclic hNK1 antagonists maintain subnanomolar hNK1 binding affinity with highly improved functional IP-1 activity (<10% SP remaining). A fused tricyclic methyl, hydroxyl geminally substituted pyrrolizinone (compound 20) had excellent functional IP (<2% SP remaining), hNK1 binding affinity, off-target selectivity, pharmacokinetic profile and in vivo activity. Complete inhibition of agonist activity was observed at both 0 and 24 h in the gerbil foot-tapping model with an ID50 of 0.02 mpk at both 0 and 24 h, respectively.

Graphical abstractPreviously, we had disclosed a novel class of hNK1 antagonists based on the 5,5-fused pyrrolidine core. These compounds displayed subnanomolar hNK1 affinity along with good efficacy in a gerbil foot-tapping (GFT) model, but unfortunately they had low to moderate functional antagonist (IP-1) activity. To elaborate on the SAR of this class of hNK1 compounds and to improve functional activity, we have designed and synthesized a new class of hNK1 antagonist with a third fused ring. Compared to the 5,5-fused pyrrolidine class, these 5,5,5-fused tricyclic hNK1 antagonists maintain subnanomolar hNK1 binding affinity with highly improved functional IP-1 activity (<10% SP remaining). A fused tricyclic methyl, hydroxyl geminally substituted pyrrolizinone (compound 20) had excellent functional IP (<2% SP remaining), hNK1 binding affinity, off-target selectivity, pharmacokinetic profile and in vivo activity. Complete inhibition of agonist activity was observed at both 0 and 24 h in the gerbil foot-tapping model with an ID50 of 0.02 mpk at both 0 and 24 h, respectively.Figure optionsDownload full-size imageDownload as PowerPoint slide